Palliative radiotherapy versus best supportive care in patients with painful hepatic cancer (CCTG HE1): a multicentre, open-label, randomised, controlled, phase 3 study.

BACKGROUND: Palliative treatment options for painful hepatic cancer can be restricted due to patients eventually becoming refractory to standard treatment. The aim of this study was to determine whether radiotherapy improves hepatic pain from cancer. METHODS: In this open-label, randomised, controlled, phase 3 trial (CCTG HE1) done in nine cancer centres across Canada, we included patients aged 18 years or older with hepatocellular carcinoma or liver metastases, who were refractory to standard treatment, with an Eastern Cooperative Oncology Group performance status of 0-3, with life expectancy of more than 3 months, and pain or discomfort at its worst in the past 24 hours on the Brief Pain Inventory (BPI) of at least 4 out of 10, which was stable for up to 7 days before randomisation. Patients were randomly assigned (1:1), via a minimisation method after stratification by centre and type of cancer (hepatocellular carcinoma vs liver metastases), to single-fraction radiotherapy (8 Gy) to the liver with 8 mg ondansetron (or equivalent) orally and 4 mg dexamethasone orally given 1-2 h before radiotherapy plus best supportive care (including non-opioid or opioid analgesia, or dexamethasone, or a combination of these) or best supportive care alone. The primary endpoint was improvement in patient-reported liver cancer pain or discomfort of at least 2 points on worst pain intensity on the BPI at 1 month after randomisation. All patients with both baseline and 1-month assessments were included in the primary endpoint analysis. Safety was assessed in all patients randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT02511522, and is complete. FINDINGS: Between July 25, 2015, and June 2, 2022, 66 patients were screened and randomly assigned to radiotherapy plus best supportive care (n=33) or best supportive care (n=33). Median age was 65 years (IQR 57-72), 37 (56%) of 66 patients were male, 29 (44%) were female, 43 (65%) had liver metastases, and 23 (35%) had hepatocellular carcinoma (data on race and ethnicity were not collected). As of data cutoff (Sept 8, 2022), median follow-up was 3·2 months (95% CI 3·0-3·4). 24 (73%) of 33 in the radiotherapy plus best supportive care group and 18 (55%) of 33 in the best supportive care only group completed baseline and 1-month assessments. An improvement in hepatic pain of at least 2 points in worst pain intensity on the BPI at 1 month was seen in 16 (67%) of 24 patients in the radiotherapy plus best supportive care group versus four (22%) of 18 patients in the best supportive care group (p=0·0042). The most common grade 3-4 adverse events within 1 month after randomisation were abdominal pain (three [9%] of 33 in the radiotherapy group vs one [3%] of 33 in best supportive care group) and ascites (two [6%] vs one [3%]). No serious adverse events or treatment-related deaths were observed. INTERPRETATION: Single-fraction radiotherapy plus best supportive care improved pain compared with best supportive care alone in patients with liver cancer, and could be considered a standard palliative treatment. FUNDING: Canadian Cancer Society.

Kinetic Profiling of RAS Mutations With Circulating Tumor DNA in the Canadian Cancer Trials Group CO.26 Trial Suggests the Loss of RAS Mutations in Neo-RAS-Wildtype Metastatic Colorectal Cancer Is Transient.

PURPOSE: In metastatic colorectal cancer (mCRC), RAS mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether RAS mutations ever become clonally undetectable. METHODS: CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. RAS mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression. RESULTS: Among the 95 patients with KRAS/NRAS mutations in their archival tumor tissue, 6.3% (6/95) had undetectable RAS mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to RAS-wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo-RAS-WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent RAS mutations (75%), P = .046. The likelihood of synchronous metastases at cancer diagnosis (33% v 63%; P = .15) or liver metastases at trial baseline (50% v 68.5%; P = .17) was not significantly different between patients with disappearing versus persistent RAS mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; P = .52) was not significantly different between those with disappearing versus persistent RAS mutations. The disappearance of RAS mutations was not associated with primary tumor sidedness (P = .41), archival BRAF/MEK/ERK-mutant status (P = .16/1.00/.09), nor baseline ctDNA HER2 amplifications (P = 1.00). CONCLUSION: We identified a 3.2%-6.3% prevalence of the neo-RAS-WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.

Plasma versus Tissue Tumor Mutational Burden as Biomarkers of Durvalumab plus Tremelimumab Response in Patients with Metastatic Colorectal Cancer in the CO.26 Trial.

PURPOSE: Tissue-derived tumor mutation burden (TMB) of ≥10 mutations/Mb is a histology-agnostic biomarker for the immune checkpoint inhibitor (ICI) pembrolizumab. However, the dataset in which this was validated lacked colorectal cancers (CRC), and there is limited evidence for immunotherapy benefits in CRC using this threshold. PATIENTS AND METHODS: CO.26 was a randomized phase II study of 180 patients, comparing durvalumab and tremelimumab (D + T, n = 119 patients) versus best supportive care (BSC; n = 61 patients). ctDNA sequencing was available for 168 patients (n = 118 D + T; n = 50), of whom 165 had evaluable plasma TMB (pTMB). Tissue sequencing was available for 108 patients. Optimal thresholds for stratifying patients based on OS were determined using a minimal P value approach. This report includes the final OS analysis. RESULTS: Tissue TMB ≥10 mutations/Mb was not predictive of benefit from D + T compared with BSC in microsatellite stable (MSS) metastatic CRC [HR, 0.71 (95% CI, 0.28-1.80); P = 0.47]. No tissue TMB threshold could identify a high TMB group that benefited from ICI. By contrast, plasma TMB (pTMB) ≥28 mutations/Mb was predictive of benefit from D + T [HR, 0.34 (95% CI, 0.13-0.85); P = 0.022], as was clonal pTMB ≥10.6 mutations/Mb [HR, 0.10 (95% CI, 0.014-0.79); P = 0.029] and subclonal pTMB ≥25.9/Mb [HR, 0.20 (95% CI, 0.061-0.69); P = 0.010]. Higher pTMB was associated with length of time on cytotoxic agents (P = 0.021) and prior anti-EGFR exposure (P = 2.44 × 10-06). CONCLUSIONS: pTMB derived from either clonal or subclonal mutations may identify a group likely to benefit from immunotherapy, although validation is required. Tissue TMB provided no predictive utility for immunotherapy in this trial.

The association of health-care contact days with physical function and survival in CCTG/AGITG CO.17.

INTRODUCTION: Although contact days-days with health-care contact outside home-are increasingly adopted as a measure of time toxicity and treatment burden, they could also serve as a surrogate of treatment-related harm. We sought to assess the association between contact days and patient-reported outcomes and the prognostic ability of contact days. METHODS: We conducted a secondary analysis of CO.17 that evaluated cetuximab vs supportive care in patients with advanced colorectal cancer. CO.17 collected European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 instrument data. We assessed the association between number of contact days in a window and changes in physical function and global health status and the association between number of contact days in the first 4 weeks with overall survival. RESULTS: There was a negative association between the number of contact days and change in physical function (per each additional contact day: at 4 weeks, 1.50-point decrease; 8 weeks, 1.06-point decrease; P < .0001 for both) but not with global health status. This negative association was seen in patients receiving cetuximab but not supportive care. More contact days in the first 4 weeks was associated with worse overall survival for all participants and patients receiving cetuximab (per each additional contact day: all participants, adjusted hazard ratio [HR] = 1.07, 95% confidence interval [CI] = 1.05 to 1.10; and cetuximab, adjusted HR = 1.08, 95% CI = 1.05 to 1.11; P < .0001 for both). CONCLUSIONS: In this secondary analysis of a clinical trial, more contact days early in the course were associated with declines in physical function and worse survival in all participants and in participants receiving cancer-directed treatment. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00079066.

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

PURPOSE: Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. EXPERIMENTAL DESIGN: Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. RESULTS: A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. CONCLUSIONS: Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

A Randomized Phase III Study of Arfolitixorin versus Leucovorin with 5-Fluorouracil, Oxaliplatin, and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer: The AGENT Trial.

PURPOSE: Suboptimal treatment outcomes with 5-fluorouracil (5-FU)/folate, the standard of care for metastatic colorectal cancer (mCRC), have generated interest in optimizing the folate. Arfolitixorin ([6R]-5,10-methylene-tetrahydrofolate) is an immediately active folate and may improve outcomes over the existing standard of care (leucovorin). EXPERIMENTAL DESIGN: AGENT was a randomized, phase III study (NCT03750786). Patients with mCRC were randomized to arfolitixorin (120 mg/m2 given as two intravenous bolus doses of 60 mg/m2) or leucovorin (400 mg/m2 given as a single intravenous infusion) plus 5-FU, oxaliplatin, and bevacizumab. Assessments were performed every 8 weeks. The primary endpoint was the superiority of arfolitixorin for overall response rate (ORR). RESULTS: Between February 2019 and April 2021, 490 patients were randomized (245 to each arm). After a median follow-up of 266 days, the primary endpoint of superiority for ORR was not achieved (48.2% for arfolitixorin vs. 49.4% for leucovorin, Psuperiority = 0.57). Outcomes were not achieved for median progression-free survival (PFS; 12.8 and 11.6 months, P = 0.38), median duration of response (12.2 and 12.9 months, P = 0.40), and median overall survival (23.8 and 28.0 months, P = 0.78). The proportion of patients with an adverse event of grade ≥3 severity was similar between arms (68.7% and 67.2%, respectively), as was quality of life. BRAF mutations and MTHFD2 expression were both associated with a lower PFS with arfolitixorin. CONCLUSIONS: The study failed to demonstrate clinical benefit of arfolitixorin (120 mg/m2) over leucovorin. However, it provides some useful insights from the first-line treatment setting, including the effect of gene expression on outcomes. SIGNIFICANCE: This phase III study compared arfolitixorin, a direct-acting folate, with leucovorin in FOLFOX plus bevacizumab in mCRC. Arfolitixorin (120 mg/m2) did not improve the ORR, potentially indicating a suboptimal dose.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). Objective: To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. Design, Setting, and Participants: In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Intervention: Durvalumab plus tremelimumab or best supportive care. Main Outcomes and Measures: Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Results: Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. Conclusions and Relevance: In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

Plasma Cetuximab Concentrations Correlate With Survival in Patients With Advanced KRAS Wild Type Colorectal Cancer.

BACKGROUND: Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity. METHODS: The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m2 intravenously followed by weekly maintenance of 250 mg/m2, plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables. RESULTS: Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea. CONCLUSION: The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.

Optimizing the number of variants tracked to follow disease burden with circulating tumor DNA assays in metastatic colorectal cancer.

Background: The number of somatic mutations detectable in circulating tumor DNA (ctDNA) is highly heterogeneous in metastatic colorectal cancer (mCRC). The optimal number of mutations required to assess disease kinetics is relevant and remains poorly understood. Objectives: To determine whether increasing panel breadth (the number of tracked variants in a ctDNA assay) would alter the sensitivity in detecting ctDNA in patients with mCRC. Design: We used archival tissue sequencing to perform an in silico assessment of the optimal number of tracked mutations to detect and monitor disease kinetics in mCRC using sequencing data from the Canadian Cancer Trials Group CO.26 trial. Methods: For each patient, 1, 2, 4, 8, 12, or 16 of the most clonal (highest variant allele frequency) somatic variants were selected from archival tissue-based whole-exome sequencing and assessed for the proportion of variants detected in matched ctDNA at baseline, week 8, and progression timepoints. Results: Data from 110 patients were analyzed. Genes most frequently encountered among the top four highest VAF variants in archival tissue were TP53 (51.9% of patients), APC (43.3%), KRAS (42.3%), and SMAD4 (9.6%). While the frequency of detecting at least one tracked variant increased when expanding beyond variant pool sizes of 1 and 2 in baseline (p = 0.0030) and progression (p = 0.0030) ctDNA samples, we observed no significant benefit to increases in variant pool size past four variants in any of the ctDNA timepoints (p < 0.05). Conclusion: While increasing panel breadth beyond two tracked variants improved variant re-detection in ctDNA samples from patients with treatment refractory mCRC, increases beyond four tracked variants yielded no significant improvement in variant re-detection.

Clinical and metabolomic characterization of Brivanib-Induced hypertension in metastatic colorectal cancer.

BACKGROUND: Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome. PATIENTS AND METHODS: Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R2 Y score = 0.89, Q2 Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found. CONCLUSION: TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.

A Bayesian approach for two-stage multivariate Mendelian randomization with mixed outcomes.

Many research studies have investigated the relationship between baseline factors or exposures, such as patient demographic and disease characteristics, and study outcomes such as toxicities or quality of life, but results from most of these studies may be problematic because of potential confounding effects (eg, the imbalance in baseline factors or exposures). It is important to study whether the baseline factors or exposures have causal effects on the clinical outcomes, so that clinicians can have better understanding of the diseases and develop personalized medicine. Mendelian randomization (MR) provides an efficient way to estimate the causal effects using genetic instrumental variables to handle confounders, but most of the existing studies focus on a single outcome at a time and ignores the correlation structure of multiple outcomes. Given that clinical outcomes like toxicities and quality of life are usually a mixture of different types of variables, and multiple datasets may be available for such outcomes, it may be much more beneficial to analyze them jointly instead of separately. Some well-established methods are available for building multivariate models on mixed outcomes, but they do not incorporate MR mechanism to deal with the confounders. To overcome these challenges, we propose a Bayesian-based two-stage multivariate MR method for mixed outcomes on multiple datasets, called BMRMO. Using simulation studies and clinical applications on the CO.17 and CO.20 studies, we demonstrate better performance of our approach compared to the commonly used univariate two-stage method.

Evaluating the Time Toxicity of Cancer Treatment in the CCTG CO.17 Trial.

PURPOSE: The time spent in pursuing treatments for advanced cancer can be substantial. We have previously proposed a pragmatic and patient-centered metric of these time costs-which we term time toxicity-as any day with physical health care system contact. This includes outpatient visits (eg, bloodwork, scans, etc), emergency department visits, and overnight stays in a health care facility. Herein, we sought to assess time toxicity in a completed randomized controlled trial (RCT). METHODS: We conducted a secondary analysis of the Canadian Cancer Trials Group CO.17 RCT that evaluated weekly cetuximab infusions versus supportive care alone in 572 patients with advanced colorectal cancer. Initial results reported a 6-week improvement in median overall survival (OS) with cetuximab (6.1 v 4.6 months). Subsequent analyses reported that benefit was restricted to patients with K-ras wild-type tumors. We calculated patient-level time toxicity by analyzing trial forms. We considered days without health care contact as home days. We compared medians of time measures across arms and stratified results by K-ras status. RESULTS: In the overall population, median time toxic days were higher in the cetuximab arm (28 v 10, P < .001) although median home days were not statistically different between arms (140 v 121, P = .09). In patients with K-ras-mutated tumors, cetuximab was associated with almost numerically equal home days (114 days v 112 days, P = .571) and higher time toxicity (23 days v 11 days, P < .001). In patients with K-ras wild-type tumors, cetuximab was associated with more home days (186 v 132, P < .001). CONCLUSION: This proof-of-concept feasibility study demonstrates that measures of time toxicity can be extracted through secondary analyses of RCTs. In CO.17, despite an overall OS benefit with cetuximab, home days were statistically similar across arms. Such data can supplement traditional survival end points in RCTs. Further work should refine and validate the measure prospectively.[Media: see text].

Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results.

PURPOSE: Organ-sparing therapy for early-stage I/IIA rectal cancer is intended to avoid functional disturbances or a permanent ostomy associated with total mesorectal excision (TME). The objective of this phase II trial was to determine the outcomes and organ-sparing rate of patients with early-stage rectal cancer treated with neoadjuvant chemotherapy followed by transanal excision surgery (TES). METHODS: This phase II trial included patients with clinical T1-T3abN0 low- or mid-rectal adenocarcinoma eligible for endoscopic resection who were treated with 3 months of chemotherapy (modified folinic acid-fluorouracil-oxaliplatin 6 or capecitabine-oxaliplatin). Those with evidence of response proceeded to transanal endoscopic surgery 2-6 weeks later. The primary end point was protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1N0/X and who avoided radical surgery. RESULTS: Of 58 patients enrolled, all commenced chemotherapy and 56 proceeded to surgery. A total of 33/58 patients had tumor downstaging to ypT0/1N0/X on the surgery specimen, resulting in an intention-to-treat protocol-specified organ preservation rate of 57% (90% CI, 45 to 68). Of 23 remaining patients recommended for TME surgery on the basis of protocol requirements, 13 declined and elected to proceed directly to observation resulting in 79% (90% CI, 69 to 88) achieving organ preservation. The remaining 10/23 patients proceeded to recommended TME of whom seven had no histopathologic residual disease. The 1-year and 2-year locoregional relapse-free survival was, respectively, 98% (95% CI, 86 to 100) and 90% (95% CI, 58 to 98), and there were no distant recurrences or deaths. Minimal change in quality of life and rectal function scores was observed. CONCLUSION: Three months of induction chemotherapy may successfully downstage a significant proportion of patients with early-stage rectal cancer, allowing well-tolerated organ-preserving surgery.

Clustering on longitudinal quality-of-life measurements using growth mixture models for clinical prognosis: Implementation on CCTG/AGITG CO.20 trial.

INTRODUCTION: Analyzing longitudinal cancer quality-of-life (QoL) measurements and their impact on clinical outcomes may improve our understanding of patient trajectories during systemic therapy. We applied an unsupervised growth mixture modeling (GMM) approach to identify unobserved subpopulations ("patient clusters") in the CO.20 clinical trial longitudinal QoL data. Classes were then evaluated for differences in clinico-epidemiologic characteristics and overall survival (OS). METHODS AND MATERIALS: In CO.20, 750 chemotherapy-refractory metastatic colorectal cancer (CRC) patients were randomized to receive Brivanib+Cetuximab (n = 376, experimental arm) versus Cetuximab+Placebo (n = 374, standard arm) for 16 weeks. EORTC-QLQ-C30 QoL summary scores were calculated for each patient at seven time points, and GMM was applied to identify patient clusters (termed "classes"). Log-rank/Kaplan-Meier and multivariable Cox regression analyses were conducted to analyze the survival performance between classes. Cox analyses were used to explore the relationship between baseline QoL, individual slope, and the quadratic terms from the GMM output with OS. RESULTS: In univariable analysis, the linear mixed effect model (LMM) identified sex and ECOG Performance Status as strongly associated with the longitudinal QoL score (p < 0.01). The patients within each treatment arm were clustered into three distinct QoL-based classes by GMM, respectively. The three classes identified in the experimental (log-rank p-value = 0.00058) and in the control arms (p < 0.0001) each showed significantly different survival performance. The GMM's baseline, slope, and quadratic terms were each significantly associated with OS (p < 0.001). CONCLUSION: GMM can be used to analyze longitudinal QoL data in cancer studies, by identifying unobserved subpopulations (patient clusters). As demonstrated by CO.20 data, these classes can have important implications, including clinical prognostication.

Circulating Tumor DNA Identifies Diverse Landscape of Acquired Resistance to Anti-Epidermal Growth Factor Receptor Therapy in Metastatic Colorectal Cancer.

PURPOSE: Anti-epidermal growth factor receptor (EGFR) antibodies are effective treatments for metastatic colorectal cancer. Improved understanding of acquired resistance mechanisms may facilitate circulating tumor DNA (ctDNA) monitoring, anti-EGFR rechallenge, and combinatorial strategies to delay resistance. METHODS: Patients with treatment-refractory metastatic colorectal cancer (n = 169) enrolled on the CO.26 trial had pre-anti-EGFR tissue whole-exome sequencing (WES) compared with baseline and week 8 ctDNA assessments with the GuardantOMNI assay. Acquired alterations were compared between patients with prior anti-EGFR therapy (n = 66) and those without. Anti-EGFR therapy occurred a median of 111 days before ctDNA assessment. RESULTS: ctDNA identified 12 genes with increased mutation frequency after anti-EGFR therapy, including EGFR (P = .0007), KRAS (P = .0017), LRP1B (P = .0046), ZNF217 (P = .0086), MAP2K1 (P = .018), PIK3CG (P = .018), BRAF (P = .048), and NRAS (P = .048). Acquired mutations appeared as multiple concurrent subclonal alterations, with most showing decay over time. Significant increases in copy-gain frequency were noted in 29 genes after anti-EGFR exposure, with notable alterations including EGFR (P < .0001), SMO (P < .0001), BRAF (P < .0001), MET (P = .0002), FLT3 (P = .0002), NOTCH4 (P = .0006), ERBB2 (P = .004), and FGFR1 (P = .006). Copy gains appeared stable without decay 8 weeks later. There were 13 gene fusions noted among 11 patients, all but one of which was associated with prior anti-EGFR therapy. Polyclonal resistance was common with acquisition of ≥ 10 resistance related alterations noted in 21% of patients with previous anti-EGFR therapy compared with 5% in those without (P = .010). Although tumor mutation burden (TMB) did not differ pretreatment (P = .63), anti-EGFR exposure increased TMB (P = .028), whereas lack of anti-EGFR exposure resulted in declining TMB (P = .014). CONCLUSION: Paired tissue and ctDNA sequencing identified multiple novel mutations, copy gains, and fusions associated with anti-EGFR therapy that frequently co-occur as subclonal alterations in the same patient.

Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial.

OBJECTIVE: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer. DESIGN: Multicentre, open label, randomised controlled trial. SETTINGS: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020. PARTICIPANTS: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection. INTERVENTIONS: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only. MAIN OUTCOME MEASURES: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population. RESULTS: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1). CONCLUSIONS: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT01455831.

The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma.

Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population (p = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group (p = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy (p = 0.001) and chemotherapy (p = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

Complementary Medicine Use Amongst Patients with Metastatic Cancer Enrolled in Phase III Clinical Trials.

BACKGROUND: Complementary medicines (CM) are frequently used by patients with cancer. Controversy exists over the effectiveness and risk that CM may add to conventional cancer therapy. The incidence of CM use among patients enrolled in phase III clinical trials is unknown. METHODS: Medication lists from 6 international phase III clinical trials were retrospectively reviewed to identify patients using CM. Patients had metastatic breast, colorectal, or lung cancers. Quality of life, adverse events, overall survival, and progression-free survival were compared between CM users and non-users. Baseline differences between groups were adjusted with propensity score matching groups. RESULTS: Seven hundred and six of 3446 patients (20.5%) used at least one CM. CM use was highest among patients with breast cancer (35.6%). CM users had more favorable baseline prognostic factors (ECOG 0-1, non-smoking status, younger age, and fewer metastases). CM use was associated with lower rates of adverse events (50% vs. 62%, P = .002) and quality of life was similar between both groups. After adjustment with propensity score matching, CM use was also associated with longer overall survival in patients with lung cancer (adjusted hazard ratio 0.80, 95%CI, 0.68-0.94, P =.0054). However, several key control variables like EGFR status were not available. CONCLUSION: One in 5 patients in phase III clinical trials report using CM. CM was not associated with worse cancer-specific outcomes. However, CM users had more favorable baseline prognostic factors, and likely other confounders that may have contributed to improved outcomes observed in the lung cohort. Physicians should monitor for CM use and potential interactions with clinical trial drugs.

Early detection of treatment futility in patients with metastatic colorectal cancer.

PURPOSE: Chemotherapy options for treating CRC have rapidly expanded in recent years, and few have predictive biomarkers. Oncologists are challenged with evidence-based selection of treatments, and response is evaluated retrospectively based on serial imaging beginning after 2-3 months. As a result, cumulative toxicities may appear in patients who will not benefit. Early recognition of non-benefit would reduce cumulative toxicities. Our objective was to determine treatment-related changes in the circulating metabolome corresponding to treatment futility. METHODS: Metabolomic studies were performed on serial plasma samples from patients with CRC in a randomized controlled trial of cetuximab vs. cetuximab + brivanib (N = 188). GC-MS quantified named 94 metabolites and concentrations were evaluated at baseline, Weeks 1, 4 and 12 after treatment initiation. In a discovery cohort (N = 68), a model distinguishing changes in metabolites associated with radiographic disease progression and response was generated using OPLS-DA. A cohort of 120 patients was used for validation of the model. RESULTS: By one week after treatment, a stable model of 21 metabolites could distinguish between progression and partial response (R2Y = 0.859; Q2Y = 0.605; P = 5e-4). In the validation cohort, patients with the biomarker had a significantly shorter OS (P < 0.0001). In a separate cohort of patients with HCC on axitinib, appearance of the biomarker also signified a shorter PFS (1.7 months vs. 9.2 months, P = 0.001). CONCLUSION: We have identified changes in the metabolome that appear within 1 week of starting treatment associated with treatment futility. The novel approach described is applicable to future efforts in developing a biomarker for early assessment of treatment efficacy.